The present invention relates to a controlled release product containing a pharmaceutical which is a gastrointestinal irritant. It also relates to a process for preparing such a product. More particularly, the present invention relates to micronized potassium chloride in a protective balm, preferably a microcapsule of micronized potassium chloride in a semi-solid balm, and a process for preparing the same.
It is well recognized that abnormally low levels of potassium chloride in the body may be caused by certain disease states or by the administration of certain therapeutic agents, such as, for example, corticosteroids, thiazide-type diuretics or other diuretics. The symptoms of this condition, hypokalemia, include muscular weakness and cardiac disturbances. Treatment of this condition normally comprises replacement of the potassium ion. In view of the fact that therapy with therapeutic agents such as those mentioned above may often be on a prolonged basis, it is often the case that potassium chloride replacement therapy must be maintained over extended periods of time.
The art is appraised of problems inherent with the administration of potassium chloride. Potassium chloride has been found to be irritating to the gastric mucosa and, therefore, be a potential source of ulceration. This has been shown to be true, for example, with enteric-coated potassium chloride tablets which have caused lesions of the lower bowel over a period of time in all probability due to irritation caused by the concentration of potassium chloride at the sites in the intestinal wall where such tablets dissolve.
There have been numerous attempts to formulate potassium chloride into dosage forms designed to overcome problems such as that described above with varying degrees of success. One approach to the formulation of potassium chloride is to compound it into a liquid formulation. Such a preparation would, for example, be advantageous in that it would be relatively free from the possibility of irritation caused by high concentration of potassium chloride at the site of dissolution of a tablet in the stomach or intestinal tract. A second obvious advantage of such liquid preparations would be acceptance by those patients who have difficulty swallowing a tablet.
However, liquid preparations have certain disadvantages. The most significant disadvantage of liquid potassium chloride preparations known heretofore is that, regardless of the type of liquid preparation or formulation thereof, such preparations do not have an acceptable taste. It is significant that attempts to date to market a liquid form of potassium chloride have not fared particularly well in comparison to commercial tablets or capsules due in the main to the inability of such liquid preparations to mask the salty, objectionable taste of potassium chloride.
For this reason, Ranucci in U.S. Pat. No. 4,259,323 proposes preparation of a better tasting, less irritating liquid emulsion of potassium chloride. Still, it is hard to effectively mask the taste of potassium chloride. Accordingly, solid potassium chloridecontaining tablets or capsules remain the dosable form of choice.
Another approach to the formulation of potassium chloride is to coat, encapsulate, or blend solid potassium chloride with a protective material. Sugar-coated tablets containing potassium chloride in a wax matrix are marketed as a slowly available potassium source. The use of a wax-like matrix is taught in Blichare U.S. Pat. No. 4,132,753, for example. Physicians Desk-Reference (1979), page 794, states "fewer bowel lesions are observed with wax-matrix tablets compared to enteric-coated potassium chloride products, but that there have been reports of upper gastrointestinal bleeding associated with the wax-matrix tablets. Use of these wax-coated products should be discontinued immediately and the possibility of bowel obstruction or perforation considered if severe vomiting, abdominal pain, distention or gastrointestinal bleeding occurs."
Because of the problem encountered with potassium chloride/wax-matrix tablets, Gallian in U.S. Pat. No. 4,140,756 proposes placing a permanent, erosion resistant polymeric film coating over a core of potassium chloride in a wax-like matrix. Release of the potassium chloride is to take place by way of diffusion of the gastric juices and intestinal fluids and potassium chloride through the polymeric film. A tablet of the type disclosed in the Gallian patent will result in controlled release of potassium chloride, so much so that large amounts of potassium chloride (preferably 900-1200 mg) are used. Large, concentrated amounts of potassium chloride, no matter how protected, still present the danger of ulceration. The tablets remain intact and may become lodged in the digestive tract, releasing large amounts of potassium chloride in a small localized area.
Gelatin capsules containing controlled release microencapsulated potassium chloride have also been proposed. See Lippmann U.S. Pat. No. 4,259,315. Testing of product produced in accordance with the Lippmann patent has shown that it is less ulcerogenic than solid enteric-coated or non-coated potassium chloride and has effects on the gut mucosa comparable to wax-matrix potassium chloride preparations. Lesion tests showed that enteric-coated potassium chloride caused marked ulceration in all instances while the product of Lippmann U.S. Pat. No. 4,259,315 produced only small local erosions. Wax-matrix potassium chloride released a considerable portion of potassium chloride contents in the stomach, caused more ulcers and erosions at that site than the product of the Lippman patent, but did not cause more distal lesions.
Most recently, it has been proposed that a wax-like material be mixed with a microencapsular material in preparing microencapsulated sustained release potassium chloride. See Roswall U.S. Pat. No. 4,574,080.
While such encapsulation systems show improved results over enteric-coated, uncoated, and wax-matrix potassium chloride preparations, they are not totally free from ulceration problems. Further improvement could be made.
Accordingly, the need exists for an improved system for controlled release of a gastrointestinal irritant drug such as potassium chloride.